The major objective of the proposed study is to investigate the role of dopamine D3 receptor mechanisms involved in methamphetamine (METH) behavioral sensitization. Stimulation of dopamine D3 receptors in the limbic/nucleus accumbens area reduces locomotor activity after acute administration. The hypothesis is that chronic METH administration results in adaptive downregulation of D3 receptors in the nucleus accumbens. And downregulation of D3 receptors is believed to play a role in METH sensitization. To test this hypothesis, we will compare the acute and chronic effects of putative D3 receptor agonist, PD 128907 and the more selective D3 agonist, 7 -OHDPAT, on METH-induced locomotor activity. To further assess the role of D3 receptors in METH sensitization, METH-induced locomotion will be compared in wildtype and D3 receptor mutant animals. The METH sensitization model, i.e. reverse tolerance paradigm, will be used to assess changes in METH-induced behaviors. Acute and chronic behavioral studies will be conducted in specific aim #1 to define the behavioral effects of selective D3 agonists on METH-induced sensitization. Behavioral studies also will be conducted in specific aim #2 to define the effects of chronic METH administration in dopamine D3 receptor mutant mice. In specific aim #3, dopamine D3 receptor mediated changes in c-fos expression will be used to assess changes in D3 neuronal function the limbic/nucleus accumbens using immunohistochemistry studies. The proposed studies will provide further insight into dopamine receptor mechanisms involved in METH sensitization. Considering that METH sensitization is used as an animal model for amphetamine psychosis, the proposed studies may also have important implications for mechanisms involved in amphetamine psychosis. Additionally, drug sensitization has been implicated in the pathology of drug addiction and drug relapse; the proposed studies may provide further insight into the mechanisms involved.